Microvascular Angina and INOCA: Diagnosis with CFR and IMR

Definition and Pathophysiology

Angina with non-obstructive coronary arteries (ANOCA) describes anginal symptoms in patients whose epicardial coronary arteries are normal or show no obstructive disease. Ischaemia with non-obstructive coronary arteries (INOCA) denotes the subgroup in whom objective myocardial ischaemia is demonstrated. ANOCA may occur in up to 70% of patients undergoing invasive coronary angiography, while approximately 25% of these patients have documented ischaemia. Among patients referred for invasive angiography, ANOCA/INOCA is more frequent in women, affecting approximately 50–70% of women compared with 30–50% of men.

Microvascular angina (MVA) is myocardial ischaemia caused by structural or functional abnormalities of the coronary microcirculation. These abnormalities may impair coronary flow reserve (CFR), reduce microcirculatory conductance, or cause abnormal vasoconstriction of coronary arterioles. Structural and functional mechanisms may coexist.

The formal diagnostic construct for MVA incorporates four components:

• Symptoms suggestive of myocardial ischaemia.

• Objective evidence of myocardial ischaemia.

• Absence of obstructive coronary artery disease, defined as no stenosis exceeding 50% diameter reduction and/or an FFR >0.80.

• Demonstration of reduced CFR and/or inducible microvascular spasm.

The microvascular circulation cannot be directly visualized in vivo in humans. Consequently, diagnosis depends on functional assessment. Coronary microvascular dysfunction (CMD) is characterized invasively by reduced CFR and increased microvascular resistance, measured by the index of microcirculatory resistance (IMR), hyperaemic microvascular resistance (HMR), or microvascular resistance reserve (MRR).

Microvascular Endotypes

Two broad CMD patterns have been described:

• Functional CMD: resting vascular tone is generally normal, but the increase in coronary blood flow during stress is inadequate.

• Structural CMD: resting vascular tone is increased, potentially reflecting capillary rarefaction, fibrosis, or left ventricular hypertrophy. Hypertension, diabetes, and elevated NT-proBNP are more frequent in this pattern.

Endothelial dysfunction may contribute to both microvascular and epicardial vasomotor disorders. Endothelial activation can promote the release of adhesion molecules, inflammatory cytokines, and vasoconstricting mediators, producing abnormal vascular responses and potentially increasing the future risk of obstructive coronary disease.

ANOCA/INOCA is heterogeneous. Potential mechanisms include:

• CMD;

• epicardial coronary vasospasm;

• microvascular spasm;

• endothelial dysfunction;

• concealed diffuse atherosclerosis;

• myocardial bridging;

• myocardial metabolic abnormalities; and

• abnormal pain perception in patients without demonstrable ischaemia.

The absence of obstructive disease therefore does not establish a benign diagnosis. ANOCA/INOCA is associated with recurrent symptoms, impaired quality of life, repeated hospital presentations and angiography, and increased short- and long-term adverse cardiovascular outcomes.

Clinical Presentation and Symptoms

Symptoms may resemble those of obstructive epicardial coronary disease or vasospastic angina. The clinical presentation is not sufficiently specific to identify the underlying mechanism. Microvascular, vasospastic, and obstructive angina may produce overlapping symptom patterns.

Patients may present with:

• exertional angina or angina-like chest discomfort;

• symptoms suggestive of myocardial ischaemia despite normal or non-obstructive coronary arteries;

• dyspnoea;

• fatigue; and

• recurrent symptoms causing impaired quality of life.

Women with suspected angina are more likely than men to have non-anginal symptoms such as dyspnoea and fatigue, as well as a greater prevalence of MVA. Symptoms may be persistent or episodic and may not follow a classical pattern of stable exertional angina.

Vasospastic angina should be suspected when patients have repetitive episodes of rest angina, particularly when symptoms are associated with transient ST-segment changes that resolve with nitrates or calcium-channel antagonists.

Psychosocial stress has also been associated with coronary vasomotor disorders. In some patients, chest discomfort occurs without objective evidence of ischaemia and may reflect abnormal pain perception or sensitivity.

Evaluation and Physical Examination

The initial clinical evaluation should establish whether symptoms are suggestive of myocardial ischaemia and should assess the likelihood of obstructive epicardial coronary disease. A normal or non-obstructive coronary angiogram does not exclude myocardial ischaemia or CMD.

Risk factors and associated conditions linked to CMD include:

• smoking;

• older age;

• diabetes;

• hypertension;

• dyslipidaemia;

• left ventricular hypertrophy;

• inflammatory diseases, including systemic lupus erythematosus and rheumatoid arthritis;

• infiltrative heart disease; and

• psychosocial stress.

Small coronary vessel size or reduced coronary lumen volume may also increase the likelihood of CMD.

The available source material does not describe specific physical-examination findings that reliably distinguish MVA, CMD, or INOCA from obstructive coronary disease. Physical examination therefore contributes to general cardiovascular assessment and evaluation of associated conditions, but functional coronary testing is required to define the coronary endotype.

Diagnostic Strategy

Initial Recognition

The combination of myocardial ischaemia on functional imaging and non-obstructive coronary arteries on coronary CT angiography (CCTA) or invasive coronary angiography should prompt consideration of ANOCA/INOCA.

First-line evaluation of suspected chronic coronary syndromes should use non-invasive anatomical or functional imaging. CCTA is preferred for excluding obstructive disease and identifying non-obstructive coronary atherosclerosis. Functional imaging is useful for correlating symptoms with myocardial ischaemia, estimating myocardial viability, and guiding management.

When an intermediate epicardial stenosis is present, anatomical severity alone is insufficient to establish functional significance. Invasive FFR or iFR should be used where appropriate. ANOCA/INOCA may coexist with diffuse atherosclerosis or intermediate lesions that are not functionally significant.

Non-invasive Assessment of Microvascular Function

Non-invasive modalities can assess coronary or myocardial flow reserve, although they do not directly visualize the coronary microcirculation.

PET permits quantification of myocardial blood flow in millilitres per minute per gram of myocardium. Myocardial flow reserve reflects the increase in myocardial blood flow produced by maximal vasodilation, typically with adenosine or regadenoson. Because the microcirculation is the principal determinant of vascular resistance, myocardial flow reserve provides an assessment of small-vessel vasodilator function.

An MFR below 2.0 is often considered abnormal on PET, although a threshold of 2.5 has been used in patients with non-obstructive CAD. Thresholds vary according to the imaging technique, and agreement between modalities is only modest. For transthoracic Doppler, a CFR below 2.5 in non-obstructive CAD indicates an abnormal microcirculatory response. Other sources note that a CFR below 2.0 has low sensitivity for CMD, whereas use of a threshold below 2.5 provides more reasonable diagnostic accuracy.

In patients with known ANOCA/INOCA, stress SPECT or PET, stress CMR, and stress echocardiography remain first-line investigations, although diagnostic yield may be limited. The current standard for comprehensive endotype characterization remains invasive coronary functional testing.

Invasive Coronary Functional Testing

Rationale

Invasive testing is the definitive approach for identifying the mechanism of ANOCA/INOCA because no available technique directly visualizes the coronary microcirculation in vivo.

Testing may combine:

• intracoronary pressure measurements;

• coronary flow measurements;

• assessment of FFR or iFR for epicardial lesions;

• CFR;

• IMR, HMR, or MRR;

• acetylcholine testing for endothelial dysfunction and vasospasm; and

• intracoronary nitroglycerine and adenosine responses.

This combined approach is often termed functional coronary angiography.

Coronary Flow Reserve

CFR describes the capacity of the coronary circulation to increase blood flow during maximal vasodilation. It can be measured by:

• bolus thermodilution;

• continuous thermodilution; or

• Doppler flow velocity.

With Doppler, CFR is calculated as the ratio of hyperaemic to baseline flow velocity. With bolus thermodilution, it is calculated from baseline and hyperaemic transit times. Continuous thermodilution uses the ratio of hyperaemic to resting absolute coronary flow.

A reduced CFR may result from:

• structural microvascular disease;

• functional microvascular dysfunction;

• endothelial dysfunction;

• increased resting flow; or

• coexisting epicardial disease.

Accordingly, CFR should not be interpreted in isolation. A low value may reflect impaired vasodilator capacity, elevated resting flow, or both.

A Doppler-derived CFR below 2.5 in non-obstructive CAD is considered abnormal. Thresholds between approximately 2.0 and 2.5 have been used across studies and modalities, but no universal cross-modality threshold exists.

Index of Microcirculatory Resistance

IMR quantifies microvascular resistance during maximal hyperaemia. It is calculated as the product of distal coronary pressure during maximal hyperaemia and the hyperaemic mean transit time.

An IMR ≥25 units indicates CMD. Increased IMR is particularly useful for identifying elevated microvascular resistance when epicardial stenoses are absent or not functionally significant.

Continuous thermodilution provides greater reproducibility than bolus thermodilution for repeated measurements. Angiography-derived IMR may permit assessment without an intracoronary pressure wire.

Other Invasive Resistance Measures

Additional indices include:

• HMR: a Doppler-derived measure; a value >2.5 mmHg/cm/s indicates increased microvascular resistance.

• MRR: considered abnormal when <2.7.

• CFR: reduced values indicate impaired vasodilator capacity but do not independently identify the structural or functional mechanism.

A typical abnormal CMD profile is therefore characterized by reduced CFR and/or increased microvascular resistance, particularly IMR ≥25.

Acetylcholine Provocation Testing

Epicardial and microvascular vasomotor function can be assessed with intracoronary acetylcholine, administered as a low-dose bolus or graded infusion followed by higher doses or grades when required.

The test can evaluate:

• endothelial dysfunction;

• microvascular spasm;

• epicardial coronary spasm; and

• endothelium-dependent vasodilation.

The LAD is generally selected because it supplies a substantial myocardial territory. Testing of the circumflex artery may be appropriate when acetylcholine is administered into the left main coronary artery. Additional right coronary testing can be considered when the initial study is negative but clinical suspicion remains high.

Acetylcholine may cause clinically important bradycardia because of its cholinergic effect on the atrioventricular node, particularly when administered in the right coronary artery or a dominant circumflex artery. Bradycardia may be mitigated by selective LAD administration, prophylactic ventricular pacing, or reducing the concentration or dose. Atropine may antagonize the bradycardic response when necessary.

The response is rapidly reversible. Intracoronary nitroglycerine can reverse acetylcholine-induced spasm and can also be used to assess endothelium-independent epicardial vasodilation.

A positive test for epicardial spasm requires:

• reproduction of symptoms;

• ischaemic ECG changes; and

• angiographic reduction in coronary lumen diameter of ≥90%.

When symptoms and ischaemic ECG changes occur without ≥90% epicardial luminal constriction, microvascular spasm is diagnosed.

Intracoronary acetylcholine boluses up to a maximum of 200 µg have been reported as safe when administered according to an appropriate protocol. The use of acetylcholine is parenteral and unlicensed, and testing should be performed by an experienced interventional cardiologist after informed consent.

After vasomotor testing, intravenous adenosine is used to assess endothelium-independent vasodilation and to measure CFR, IMR, HMR, or MRR. Papaverine may be used when adenosine is contraindicated, although precautions are required because of the risk of polymorphic ventricular tachycardia.

Integrated Endotype Interpretation

A simplified invasive framework is shown below.

The specific thresholds and their interpretation depend on the measurement technique. CFR and IMR should therefore be interpreted within the complete anatomical, physiological, symptomatic, and ECG context.

Biomarkers and Laboratory Findings

The available source material does not provide a routine biomarker profile for MVA or INOCA. CMD has been associated with elevated NT-proBNP in patients with structural microvascular disease, particularly when compared with functional CMD, but NT-proBNP is not presented as a diagnostic criterion.

Risk-factor assessment should include evaluation and management of hypertension, dyslipidaemia, diabetes, and smoking. The source material does not specify additional laboratory tests or diagnostic cut-offs for these conditions in the assessment of MVA.

Treatment and Management

General Principles

Management should be patient-centred and multidisciplinary. The objectives are to:

• improve symptoms and quality of life;

• reduce recurrent healthcare utilization;

• address endothelial dysfunction and atherosclerotic risk;

• prevent myocardial ischaemia; and

• reduce adverse cardiovascular outcomes where possible.

Treatment should be guided by the identified coronary functional endotype rather than by the angiographic appearance alone.

Lifestyle counselling is warranted because coronary atherosclerosis and endothelial dysfunction are common even in patients without obstructive disease. Management of hypertension, dyslipidaemia, diabetes, and smoking should follow the relevant clinical practice guidelines. Exercise recommendations should be consistent with those used for long-standing chronic coronary syndromes.

The evidence base for pharmacological treatment remains limited, and randomized trials are lacking for many therapeutic approaches. A stratified antianginal strategy based on invasive coronary functional testing has been associated with improved angina and quality of life compared with standard, non-stratified treatment.

Treatment According to Endotype

CMD with Reduced CFR and/or Increased IMR

In patients with MVA and reduced CFR and/or increased IMR, therapies used include:

• beta-blockers;

• calcium-channel blockers;

• ranolazine; and

• ACE inhibitors.

Anti-ischaemic therapy should aim to prevent demand-related myocardial ischaemia. Amlodipine or ranolazine has been associated with improved exercise time in this setting.

Endothelial Dysfunction

ACE inhibitors should be considered for symptom control in patients with endothelial dysfunction. Risk-factor modification and preventive therapy remain important because endothelial dysfunction may coexist with diffuse or non-obstructive atherosclerosis.

Epicardial or Microvascular Spasm

Calcium-channel antagonists are first-line therapy when epicardial or microvascular spasm is demonstrated by acetylcholine testing. They are recommended to control symptoms and prevent ischaemia and potentially fatal complications.

In severe vasospastic angina, substantially higher doses may be required. Diltiazem may be given at 200 mg twice daily or increased up to 960 mg daily. Combination treatment with a non-dihydropyridine calcium-channel blocker such as diltiazem and a dihydropyridine agent such as amlodipine may be necessary.

Nitrates should be considered to prevent recurrent episodes. Nicorandil, which combines nitrate-like and potassium-channel activation, may be an alternative, although adverse effects are frequent.

Overlapping Endotypes

When more than one mechanism is present, combination treatment with nitrates, calcium-channel blockers, and other vasodilators may be considered. Such therapy should be tailored to the documented physiology, symptom burden, blood pressure, heart rate, and tolerance.

Refractory Symptoms

Ranolazine may be used as an antianginal treatment. Its described mechanism is improvement of myocyte relaxation and ventricular compliance by reducing sodium and calcium overload.

Spinal cord stimulation is an option for patients who remain refractory despite medical therapy.

A coronary sinus reducer may be considered in experienced centres for patients with debilitating angina and obstructive CAD that remains refractory to optimal medical and revascularization strategies. This intervention is not presented as a routine treatment for MVA or INOCA without obstructive disease.

Guideline Recommendations

The principal recommendations are summarized below.

Relationship to MINOCA

INOCA should be distinguished from myocardial infarction with non-obstructive coronary arteries (MINOCA). MINOCA is a clinical working diagnosis in a patient with symptoms suggestive of acute coronary syndrome, troponin elevation, and no epicardial stenosis ≥50% at angiography.

MINOCA has multiple possible coronary and non-coronary causes. If invasive angiography does not establish the cause, further assessment may include:

• left ventriculography;

• left ventricular end-diastolic pressure measurement;

• coronary microvascular and vasoreactivity testing;

• intravascular imaging;

• echocardiography;

• CT; and

• CMR.

CMR is a key investigation and should be performed as soon as possible, ideally during the index admission, when the diagnosis remains uncertain after angiography. Management should follow the final established diagnosis rather than the initial working label of MINOCA.

Prognosis and Follow-up

ANOCA/INOCA is associated with increased morbidity and mortality, impaired quality of life, recurrent angina, repeated hospitalization, and increased use of coronary angiography. The prognosis is heterogeneous and depends on the underlying endotype.

Reduced CFR has prognostic significance. In patients with angina and angiographically normal coronary anatomy, impaired CFR has been associated with increased cardiovascular events. Epicardial vasoconstriction has been associated with hospitalization for angina.

Patients with persistently symptomatic disease require reassessment of:

• symptom burden and quality of life;

• adherence and response to endotype-directed therapy;

• blood pressure, diabetes, dyslipidaemia, and smoking;

• adverse drug effects;

• recurrent rest symptoms or transient ECG changes; and

• the need for further functional testing.

A persistently symptomatic patient with poor quality of life despite medical therapy should undergo invasive coronary functional testing if this has not already been performed. Establishing the endotype is important because untreated CMD or vasospasm may lead to recurrent symptoms, repeated investigations, and inappropriate or ineffective therapy.

Long-term follow-up should combine symptom-guided antianginal treatment with cardiovascular prevention, lifestyle counselling, and patient-centred shared decision-making.